Objective This study aimed to conduct a preliminary study on the possible role and significance of interleukin (IL)-12 and IL-27 in the pathogeneses of oral lichen planus (OLP). Methods Thirty cases of patients with OLP (fifteen cases of reticular OLP and fifteen cases of erosive OLP) were enrolled in this study, and twenty cases of healthy people served as controls. Lymphocyte subsets CD3+, CD4+, CD8+, CD19+, and CD16+56 [natural killer cell (NK)] were tested using flow cytometry, and humoral immunity [immunoglobulin (Ig)G, IgA, IgM, C3, C4] were examined using nephelometry assays. IL-12 and IL-27 contents in serum of patients with OLP and normal controls were detected through enzyme linked immunosorbent assay. The correlations between the levels of IL-12, IL-27, immune status, and clinical characteristics of patients with OLP were analyzed, respectively. Results CD3+, CD4+, and CD8+ in patients with OLP were markedly lower than the normal value, whereas CD19+ of OLP in patients was significantly higher than the normal value (P<0.05). IgM in patients with OLP was increased, whereas C4 was declined (P<0.05). IL-12 and IL-27 levels showed significant upregulation of OLP patients compared with control groups (P<0.05). Meanwhile, positive correlations existed between IL-12 and IL-27 levels in the serum of patients with OLP (r=0.912, P<0.01). No significant correlations of IL-12 and IL-27 expressions with clinical characteristics of OLP were found (P>0.05). Negative correlations of IL-12 and IL-27 levels with CD16+56(NK) cells were observed (r1=-0.416, P1=0.022; r2=-0.392, P2=0.032, respectively), whereas a positive correlation existed for IgG (r1=0.445, P1=0.014; r2=0.549, P2=0.002, respectively). Conclusion A cellular immune dysfunction mainly dominate in patients with OLP, accompanied by some degree of humoral-immunity-function disorder. The abnormally high expressions of IL-12 and IL-27 are possibly synergized and promoted inflammation development in OLP. Its promotion takes place through the negative feedback regulation of humoral immune responses, which are involved in the regulation of immune mechanisms of OLP.